| Reference | [1]. Front Neurol. 2019 Jun 28;10:519. doi: 10.3389/fneur.2019.00519. eCollection 2019.<br />
The Selective HDAC6 Inhibitor ACY-738 Impacts Memory and Disease Regulation in an Animal Model of Multiple Sclerosis.<br />
LoPresti P(1).<br />
Author information: (1)Department of Psychology, University of Illinois at Chicago, Chicago, IL, United States.<br />
Multiple sclerosis (MS) is a complex disease characterized by autoimmune demyelination and progressive neurodegeneration. Pathogenetic mechanisms of the disease remain largely unknown. Changes in synaptic functions have been reported; however, the significance of such alterations in the disease course remains unclear. Furthermore, the therapeutic potential of targeting synapses is not well-established. Synapses have key signaling elements that regulate intracellular transport and overall neuronal health. Histone deacetylase (HDAC)6 is a microtubule-associated deacetylase. The interaction between HDAC6 and microtubules is augmented by HDAC6 inhibitors. In this study, experimental autoimmune encephalomyelitis (EAE) mice, an animal model of MS, were treated with the HDAC6 inhibitor drug ACY-738 (20 mg/kg) on day 9 and day 10 post-immunization. Mice were assessed for working memory using the cross-maze test at 10 days post-immunization (d.p.i.), whereas disease scores were recorded over approximately 4 weeks post-immunization. We observed that ACY-738 delayed disease onset and reduced disease severity. Most importantly, ACY-738 increased short-term memory in a manner sensitive to disease severity. We induced EAE disease with various amounts of myelin oligodendrocyte glycoprotein (MOG35-55). EAE mice receiving 100 μg of MOG35-55 and treated with ACY-738 had a statistically significant increase in short term-memory compared to naive mice. Additionally, EAE mice receiving 50 μg MOG35-55 and treated with ACY-738 had a statistically significant increase in short term-memory when compared to EAE mice without drug treatment. In contrast, ACY-738 did not change short-term memory in EAE mice immunized with 200 μg of MOG35-55. Because ACY-738 increases short-term memory only with lower amounts of EAE-inducing reagents, we hypothesize that the inflammatory-demyelinating environment induced by higher amount of EAE-inducing reagents overpowers (at day 10 post-immunization) the synaptic molecules targeted by ACY-738. These studies pave the way for developing ACY-738-like compounds for MS patients and for using ACY-738 as a probe to elucidate disease-sensitive changes at the synapses occurring early in the disease course.<br />
DOI: 10.3389/fneur.2019.00519 PMCID: PMC6609573 PMID: 31316445<br />
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[2]. Clin Immunol. 2016 Jan;162:58-73. doi: 10.1016/j.clim.2015.11.007. Epub 2015 Nov 22.<br />
Specific HDAC6 inhibition by ACY-738 reduces SLE pathogenesis in NZB/W mice.<br />
Regna NL(1), Vieson MD(1), Luo XM(1), Chafin CB(1), Puthiyaveetil AG(2), Hammond SE(1), Caudell DL(3), Jarpe MB(4), Reilly CM(5).<br />
Author information: (1)Department of Biomedical Sciences & Pathobiology, Virginia-Maryland Regional College of Veterinary Medicine, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061, United States. (2)Department of Biotechnology, American University of Ras Al Khaimah, United Arab Emirates. (3)Wake Forest University Primate Center, Department of Pathology/Comparative Medicine, Wake Forest School of Medicine, Winston-Salem, NC 27157, United States. (4)Acetylon Pharmaceuticals, Inc., 70 Fargo St., Boston, MA 02210, United States. (5)Department of Biomedical Sciences & Pathobiology, Virginia-Maryland Regional College of Veterinary Medicine, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061, United States; Edward Via College of Osteopathic Medicine, Blacksburg, VA 24060, United States. Electronic address: [email protected].<br />
We sought to determine if a selective HDAC6 inhibitor (ACY-738) decreases disease in NZB/W mice. From 22 to 38weeks-of-age, mice were injected intraperitoneally with 5 or 20mg/kg of ACY-738, or vehicle control. Body weight and proteinuria were measured every 2weeks, while sera anti-dsDNA, Ig isotypes, and cytokine levels were measured every 4weeks. Kidney disease was determined by evaluation of sera, urine, immune complex deposition, and renal pathology. Flow cytometric analysis assessed thymic, splenic, bone marrow, and peripheral lymphocyte differentiation patterns. Our results showed HDAC6 inhibition decreased SLE disease by inhibiting immune complex-mediated glomerulonephritis, sera anti-dsDNA levels, and inflammatory cytokine production and increasing splenic Treg cells. Inhibition of HDAC6 increased the percentage of cells in the early-stage developmental fractions of both pro- and pre-B cells. These results suggest that specific HDAC6 inhibition may be able to decrease SLE disease by altering aberrant T and B cell differentiation.<br />
DOI: 10.1016/j.clim.2015.11.007 PMID: 26604012 [Indexed for MEDLINE]<br />
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[3]. Alzheimers Dement (N Y). 2015 Oct 11;1(3):170-181. doi: 10.1016/j.trci.2015.08.001. eCollection 2015 Nov.<br />
Pharmocologic treatment with histone deacetylase 6 inhibitor (ACY-738) recovers Alzheimer's disease phenotype in amyloid precursor protein/presenilin 1 (APP/PS1) mice.<br />
Majid T(1), Griffin D(1), Criss Z 2nd(1), Jarpe M(2), Pautler RG(1)(3)(4).<br />
Author information: (1)Interdepartmental Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, TX, USA. (2)Acetylon Pharmaceuticals, Boston, MA, USA. (3)Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX, USA. (4)Department of Neuroscience, Baylor College of Medicine, Houston, TX, USA.<br />
INTRODUCTION: Current therapy for Alzheimer's disease (AD) focuses on delaying progression, illustrating the need for more effective therapeutic targets. Histone deacetylase 6 (HDAC6) modulates tubulin acetylation and has been implicated as an attractive target. HDAC6 is also elevated in postmortem tissue samples from patients. However, HDAC6 inhibitors have had limited success preclinically due to low blood-brain barrier penetration. METHOD: We investigated a specific, potent HDAC6 inhibitor (ACY-738) in a mouse model of AD. We determined the effects of ACY-738 treatment on axonal transport, behavior, and pathology in amyloid precursor protein/presenilin 1 mice. RESULTS: We demonstrated improvements in in vivo axonal transport in two treatment groups as a result of ACY-738 brain levels. We also demonstrated recovery of short-term learning and memory deficits, hyperactivity, and modifications of tau and tubulin. DISCUSSION: Our findings implicate specific, targeted HDAC6 inhibitors as potential therapeutics and demonstrate that further investigations are warranted into effects of HDAC6 inhibitors in AD.<br />
DOI: 10.1016/j.trci.2015.08.001 PMCID: PMC5975056 PMID: 29854936<br />
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[4]. Neuropsychopharmacology. 2014 Jan;39(2):389-400. doi: 10.1038/npp.2013.207. Epub 2013 Aug 19.<br />
Antidepressant-like properties of novel HDAC6-selective inhibitors with improved brain bioavailability.<br />
Jochems J(1), Boulden J(1), Lee BG(2), Blendy JA(2), Jarpe M(3), Mazitschek R(4), Van Duzer JH(3), Jones S(3), Berton O(1).<br />
Author information: (1)Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. (2)Department of Pharmacology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. (3)Acetylon Pharmaceuticals, Boston, MA, USA. (4)Center for Systems Biology, Massachusetts General Hospital, Boston, MA, USA.<br />
HDAC inhibitors have been reported to produce antidepressant and pro-cognitive effects in animal models, however, poor brain bioavailability or lack of isoform selectivity of current probes has limited our understanding of their mode of action. We report the characterization of novel pyrimidine hydroxyl amide small molecule inhibitors of HDAC6, brain bioavailable upon systemic administration. We show that two compounds in this family, ACY-738 and ACY-775, inhibit HDAC6 with low nanomolar potency and a selectivity of 60- to 1500-fold over class I HDACs. In contrast to tubastatin A, a reference HDAC6 inhibitor with similar potency and peripheral activity, but more limited brain bioavailability, ACY-738 and ACY-775 induce dramatic increases in α-tubulin acetylation in brain and stimulate mouse exploratory behaviors in novel, but not familiar environments. Interestingly, despite a lack of detectable effect on histone acetylation, we show that ACY-738 and ACY-775 share the antidepressant-like properties of other HDAC inhibitors, such as SAHA and MS-275, in the tail suspension test and social defeat paradigm. These effects of ACY-738 and ACY-775 are directly attributable to the inhibition of HDAC6 expressed centrally, as they are fully abrogated in mice with a neural-specific loss of function of HDAC6. Furthermore, administered in combination, a behaviorally inactive dose of ACY-738 markedly potentiates the anti-immobility activity of a subactive dose of the selective serotonin reuptake inhibitor citalopram. Our results validate new isoform-selective probes for in vivo pharmacological studies of HDAC6 in the CNS and reinforce the viability of this HDAC isoform as a potential target for antidepressant development.<br />
DOI: 10.1038/npp.2013.207 PMCID: PMC3870780 PMID: 23954848 [Indexed for MEDLINE]<br />
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[5]. Psychopharmacology (Berl). 2020 Jul;237(7):2139-2149. doi: 10.1007/s00213-020-05525-9. Epub 2020 May 9.<br />
HDAC6-selective inhibitors decrease nerve-injury and inflammation-associated mechanical hypersensitivity in mice.<br />
Sakloth F(1), Manouras L(1), Avrampou K(1), Mitsi V(1), Serafini RA(1), Pryce KD(1), Cogliani V(1), Berton O(1)(2), Jarpe M(3), Zachariou V(4)(5).<br />
Author information: (1)Nash Family Department of Neuroscience, and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, 1425 Madison Ave, Box 10-65, New York, NY, 10029, USA. (2)Division of Neuroscience & Behavior, National institute on Drug Abuse (NIDA), 6001 Executive Blvd, Rm 4289, Rockville, MD, 20852, USA. (3)Regenacy Pharmaceuticals, 303 Wyman St, Suite 300, Waltham, MA, USA. (4)Nash Family Department of Neuroscience, and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, 1425 Madison Ave, Box 10-65, New York, NY, 10029, USA. [email protected]. (5)Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, 1425 Madison Ave, New York, NY, 10029, USA. [email protected].<br />
BACKGROUND: HDAC6 is a class IIB histone deacetylase expressed at many levels of the nociceptive pathway. This study tested the ability of novel and selective HDAC6 inhibitors to alleviate sensory hypersensitivity behaviors in mouse models of peripheral nerve injury and peripheral inflammation. METHODS: We utilized the murine spared nerve injury (SNI) model for peripheral nerve injury and the Complete Freund's Adjuvant (CFA) model of peripheral inflammation. We applied the Von Frey assay to monitor mechanical allodynia. RESULTS: Using the SNI model, we demonstrate that daily administration of the brain-penetrant HDAC6 inhibitor, ACY-738, abolishes mechanical allodynia in male and in female mice. Importantly, there is no tolerance to the antiallodynic actions of these compounds as they produce a consistent increase in Von Frey thresholds for several weeks. We observed a similar antiallodynic effect when utilizing the HDAC6 inhibitor, ACY-257, which shows limited brain expression when administered systemically. We also demonstrate that ACY-738 and ACY-257 attenuate mechanical allodynia in the CFA model of peripheral inflammation. CONCLUSIONS: Overall, our findings suggest that inhibition of HDAC6 provides a promising therapeutic avenue for the alleviation of mechanical allodynia associated with peripheral nerve injury and peripheral inflammation.<br />
DOI: 10.1007/s00213-020-05525-9 PMCID: PMC7470631 PMID: 32388618 [Indexed for MEDLINE]
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